DESCRIPTION: Several molecules which are produced by the adipose tissue are potential mediators of abnormal lipid metabolism and insulin action commonly associated with obesity. However, the molecular basis of the action of these molecules and potential interactions between then have not been clearly understood. The interactive actions of leptin and tumor necrosis factor alpha (TNFa) in relation to energy metabolism using both in vitro and in vivo experimental systems will be examined in this project. Preliminary studies showed that leptin mRNA expression and protein secretion were regulated by TNF. The observations that TNF affects leptin secretion is novel and will be the focus of these studies. An adipocyte cell line from a mouse model which does not have any functional receptor for TNF, expresses leptin mRNA and secrete readily detectable amounts of leptin protein will be used to study the components of the signalling pathway that lead to secretion of leptin. First, activated by TNF through this receptor will be assessed using leptin expression targeted null mutation of the TNFa gene show the complete absence of TNF. These animals were protected from the insulin resistance and dyslipidemia associated with high fat diet-induced obesity. The metabolic state of these animals will be characterized in detail and the role of TNF in regulating insulin action and leptin biology in vivo will be assessed in this model.